REGULATION OF EXTRACELLULAR EXCITOTOXINS

细胞外兴奋毒素的调节

基本信息

批准号：
3416784
负责人：
Michael Byrne Robinson
金额：
$ 15.8万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-01-01 至 1995-12-31
项目状态：
已结题

项目摘要

The amino acids, glutamate and aspartate, are the predominant excitatory neurotransmietters in the central nervous system. The levels of both of these amino acids approach 10 mmol/kg in brain tissue. Under normal conditions, the extracellular concentrations are maintained below .001-.010 M. In many acute neurologic diseases, including ischemia, head trauma, and epilepsy, the extracellular concentrations of these amino acids increase dramatically and the subsequent excessive activation of receptors contributes to the pathophysiology. Many investigators have focused on the postsynaptic mechanisms involved in this "excitotoxicity". The transport process that regulates the extracellular concentration of these amino acids is not well characterized. It is known that the extracellular concentrations of glutamate and aspartate are maintained at low levels by a sodium-dependent high affinity transport process. Data support the presence of at least two subtypes of this transport process with heterogeneous distributions. Studies will be carried out to test the hypotheses that there are subtypes of transport, that these subtypes have different distributions and that these subtypes can be independently regulated. Biochemical, pharmacological, and morphological techniques will be used to characterize these subtypes of transport and their regulation. The long-term goal of these studies is to define the functional relevance of these subtypes of transport systems. The objective of these studies are: 1) To compare the kinetic properties, the ion-dependence, the inhibition by excitatory amino acid analogs, and the sensitivity to sulfhydryl modifying reagents of the transport subtypes. 2) To determine the regional and cellular distribution of these subtypes of transport. 3) To characterize the mechanism(s) that regulate transport activity, including regulation by second messenger systems, including the phosphoinositide and cAMP cascades and regulation by its substrates. Subtypes of transport systems may provide a mechanism for specificity and regulation of synaptic transmission analogous to the specificity of postsynaptic signaling provided by receptor subtypes. Consistent with the diverse functions of these amino acids, metabolic and neurotransmitter pools of the excitatory amino acids are regulated independently in brain tissue. Heterogeneity of the excitatory amino acid transport systems may provide a mechanism for compartmentalization and regulation of excitatory amino acid metabolish. Characterization of the excitatory amino acid transport system(s) will help to define the role of this transport system in synaptic signaling, metabolic compartmentalization, and excitotoxic neuronal degeneration.

氨基酸，谷氨酸和天冬氨酸是主要的中枢神经系统中的兴奋性神经传递。这这两种氨基酸的水平接近大脑10 mmol/kg 组织。在正常条件下，细胞外浓度为在许多急性神经系统疾病中保持低于.001-.010 M. 包括缺血，头部外伤和癫痫，细胞外这些氨基酸的浓度急剧增加，并且随后的过度激活受体有助于病理生理学。许多调查人员专注于突触后这种“兴奋性毒性”涉及的机制。运输过程调节这些氨基酸的细胞外浓度是表现不佳。众所周知，谷氨酸和天冬氨酸由钠依赖性高保持低水平亲和力运输过程。数据支持至少两个该运输过程的亚型具有异质分布。将进行研究以检验有假设这些亚型具有不同分布的运输亚型这些亚型可以独立调节。生化，药理和形态学技术将用于表征这些运输的亚型及其调节。这这些研究的长期目标是定义功能相关性这些运输系统的亚型。这些研究的目的是：1）比较动力学特性，离子依赖性，兴奋性氨基酸类似物的抑制作用，以及对磺胺修饰的转运亚型试剂。 2）到确定这些亚型的区域和细胞分布运输。 3）表征调节运输的机制活动，包括对第二会员系统的监管，包括磷酸肌醇和cAMP级联和调节基材。运输系统的子类型可以为特异性提供机制和调节突触传播类似于特异性的受体亚型提供的突触后信号传导。持续的这些氨基酸，代谢和调节兴奋性氨基酸的神经递质池独立于脑组织。兴奋性氨基的异质性酸转运系统可能会提供隔室化的机制和兴奋性氨基酸代谢的调节。表征兴奋性氨基酸传输系统的含义将有助于定义该运输系统在突触信号，代谢中的作用分室化和兴奋性神经元变性。